PML-RARA–targeted DNA vaccine induces protective immunity in a mouse model of leukemia

Abstract

Despite improved molecular characterization of malignancies and development of targeted therapies, acute leukemia is not curable and few patients survive more than 10 years after diagnosis. Recently, combinations of different therapeutic strategies (based on mechanisms of apoptosis, differentiation and cytotoxicity) have significantly increased survival. To further improve outcome, we studied the potential efficacy of boosting the patient's immune response using specific immunotherapy. In an animal model of acute promyelocytic leukemia, we developed a DNA-based vaccine by fusing the human promyelocytic leukemia–retinoic acid receptor-α (PML-RARA) oncogene to tetanus fragment C (FrC) sequences. We show for the first time that a DNA vaccine specifically targeted to an oncoprotein can have a pronounced effect on survival, both alone and when combined with all-trans retinoic acid (ATRA). The survival advantage is concomitant with time-dependent antibody production and an increase in interferon-γ (IFN-γ). We also show that ATRA therapy on its own triggers an immune response in this model. When DNA vaccination and conventional ATRA therapy are combined, they induce protective immune responses against leukemia progression in mice and may provide a new approach to improve clinical outcome in human leukemia.

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Figure 1: PML-RARA DNA vaccination protects against disease progression.
Figure 2: Effect of RAR-α antibody production on survival.
Figure 3: Effect of PML-RARA DNA vaccination on CD4+ and CD8+ T-cell numbers, cytokine secretion and survival.

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Acknowledgements

We thank P. Chambon and C. Rochette-Egly for the RAR-α antibodies and GST-RAR-α plasmid, H. de Thé for the full-length PML-RARA construct and N. Westwood for help in preparing the manuscript. Financial support was provided by the Leukaemia Research Fund of Great Britain (R.A.P. and F.S.), the Welsh Bone Marrow Transplant Research Fund of Great Britain (R.A.P.), the Fulbright Commission (R.A.P.), the French Fondation pour la Recherche Medicale (R.A.P.), the French Association de Recherche contre le Cancer (C.C. and P.R.), the French Ligue Nationale contre le Cancer (R.A.P. and C.C.), the Fondation Saint-Louis (J.L.), the Fondation de France (M.H.S.), the Kay Kendall Leukaemia Fund (R.A.P. and S.M.), Eli Lilly (R.A.P. and T.H.P.), INSERM (R.A.P., M.P., H.T., D.C. and C.C.) and the National Institutes of Health (J.M.B.).

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Correspondence to Rose Ann Padua.

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Padua, R., Larghero, J., Robin, M. et al. PML-RARA–targeted DNA vaccine induces protective immunity in a mouse model of leukemia. Nat Med 9, 1413–1417 (2003). https://doi.org/10.1038/nm949

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